Coordinated entry and progression through the cell cycle is critical for normal function and replication of all cells; a defect in one or several of the steps that control cell cycle progression can lead alternatively to cell death or neoplasia. The fidelity of transit through the cell cycle and cellular replication are largely dependent on a regulatory network whose key components are protein kinases composed of members of the cyclin dependent kinase (cdk) family bound to specific cyclins. The objectives of this proposal are to define the roles of cdk's expressed during G0-G1 and G1-S transitions, and during progression though G1 in normal human lymphocytes. The experiments will include a multi-tiered approach using pharmacological or biological agents designed to mediate cell cycle arrest at defined stages, or to act as specific agonists or antagonists of the individual proteins under study. This application proposes to support these studies through the two-phase mechanism of a Clinical Investigator Development Award. The training phase of the project (phase I), will provide Dr. Modiano with a traditional post-doctoral experience to allow him to re-acquaint himself with familiar laboratory techniques and to learn new ones in a supervised environment. Dr. Modiano also will participate in other laboratory-related activities including weekly laboratory meetings, seminars, and journal clubs; Institute-wide Research in Progress seminars; and biweekly cell cycle meetings. These forums will provide both formal and informal settings where he will have the opportunity to discuss his research and pertinent contemporary topics in cell biology. This phase will be designed to allow Dr. Modiano to refine the research and communication skills, as well as the focused and disciplined thinking necessary to conduct independent research in the areas of hemopathology and cell growth regulation. The research started in phase I will continue into phase Il, which also will provide a transition period for Dr. Modiano to initiate his own independent research. The specific aims of this project are to: l) determine the kinetics of, and the signaling requirements (i.e., antigen or cytokine receptor- dependent) for the expression and activity of cdk2 and cdk4 in human T cells, and 2) determine the precise roles of cdk2 and cdk4 during G1 entry and progression in lymphocytes by genetic manipulation.